High-fat diet promotes colorectal cancer via carnitine/acetylcarnitine-driven CPT1A metabolic reprogramming and the intervention of β-hydroxybutyrate.

Colorectal cancer (CRC) represents the third most prevalent malignancy and the second leading cause of cancer mortality worldwide. Metabolic dysregulation is critically involved in CRC pathogenesis. Functional metabolomics aims to translate metabolite biomarkers into mechanistic insights. In this study, comprehensive metabolomic profiling of 1257 participants across discovery and validation cohorts identified β-hydroxybutyrate, carnitine, and acetylcarnitine as potential early diagnostic biomarkers for CRC. This panel demonstrated robust diagnostic performance, achieving 88.79% sensitivity and 95% specificity in an independent validation set of 400 samples. Utilizing an AOM/DSS-induced mouse model under control or high-fat diet conditions, elevated carnitine and acetylcarnitine levels were shown to originate primarily from dietary intake. In vivo and in vitro analyses revealed that these metabolites drive oncogenic metabolic reprogramming via upregulated CPT1A expression, thereby accelerating CRC progression. Immunoprecipitation assays indicated carnitine and acetylcarnitine treatment increased PPARγ while decreasing FXR expression. Conversely, the FXR agonist GW4064 or β-hydroxybutyrate elevated FXR and suppressed PPARγ. Furthermore, β-hydroxybutyrate counteracted the proliferative effects of carnitine and acetylcarnitine by activating FXR and modulating the PPARγ/PGC1α/CPT1A axis. Genetic silencing of CPT1A or β-hydroxybutyrate administration inhibited the PI3K/AKT pathway, restored intestinal barrier function, attenuated inflammation, and significantly suppressed CRC advancement. These findings elucidate a novel mechanism whereby β-hydroxybutyrate attenuates high-fat diet-associated CRC through FXR signaling modulation, revealing promising metabolic strategies for CRC prevention.